Journal of Toxicology and Environmental Health

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Influence of mineral dust surface chemistry on eicosanoid production by the alveolar macrophage Douglas C. Kuhn & Laurence M. Demers To cite this article: Douglas C. Kuhn & Laurence M. Demers (1992) Influence of mineral dust surface chemistry on eicosanoid production by the alveolar macrophage, Journal of Toxicology and Environmental Health, 35:1, 39-50, DOI: 10.1080/15287399209531592 To link to this article: http://dx.doi.org/10.1080/15287399209531592

Published online: 15 Oct 2009.

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INFLUENCE OF MINERAL DUST SURFACE CHEMISTRY ON EICOSANOID PRODUCTION BY THE ALVEOLAR MACROPHAGE Douglas C. Kuhn, Laurence M. Demers

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Department of Pathology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania

It has been suggested that radicals on the surface of dust particles are key chemical factors in the pathophysiology that results from the occupational inhalation of coal and silica dust. In addition, oxygenated derivatives of arachidonic acid (eicosanoids) have been implicated as important biochemical mediators of mineral dust-induced lung disease through their role in bronchial and vascular smooth muscle reactivity, inflammation, and fibrosis. Therefore, we assessed eicosanoid production by the rat alveolar macrophage (AM) exposed in vitro to mineral dusts with varying surface chemical characteristics in order to determine if radicals associated with the mineral dust could influence the production of proinflammatory mediators in the lung environment. Primary cultures of rat AM were exposed to freshly fractured or "stale" bituminous coal dust, as well as untreated silica or silica calcined to 500 and 1100°C. Prostaglandin E2 (PGE2), thromboxane A2 (TXA2), and leukotriene B4 (LTB4) levels in incubation medium were determined by specific radioimmunoassay. When AM were exposed to freshly fractured coal dust, PGE2 production was markedly increased. In contrast, exposure of AM to "stale" dust significantly reduced PGE2 production. Exposure of AM to freshly fractured coal dust resulted in a significant increase in production by AM, while exposure to stale coal dust did not influence AM TXA2 production. Neither "fresh" nor "stale" coal dust had any effect on LTB4 production. In vitro exposure of AM to untreated silica resulted in a significant increase in TXA2 PCE^ TXA2, and LTB4 production compared with control. However, exposure of AM to silica calcined to 1100°C resulted in eicosanoid levels that were not significantly different from control. These effects were still apparent 8 wk after calcination of the silica particles. Silica was a more potent activator of AM eicosanoid production than was coal, and amorphous fumed silica was a more potent activator of AM eicosanoid production than was crystalline silica. These findings suggest that radicals associated with respirable coal and silica particles may play a key role in the ability of mineral dust to activate AM eicosanoid production and therefore may be important in the pathophysiological consequences of occupational mineral dust inhalation.

The authors thank Barbara Scheetz for expert technical assistance and Dr. Pedro Bolsaitis (Massachusetts Institute of Technology) for provision of silica dusts. This research was supported by the U.S. Department of the Interior's Mineral Institute Program administered through the Generic Technology Center for Respirable Dust under Grant 1135142. Requests for reprints should be sent to Dr. Douglas C. Kuhn, Department of Pathology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033.

39 Journal of Toxicology and Environmental Health, 35:39-50, 1992 Copyright © 1992 by Hemisphere Publishing Corporation

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INTRODUCTION The phagocytosis of inhaled particles by the alveolar macrophage (AM) results in a defensive reaction that includes lysosomal enzyme release, the generation of reactive oxygen species, and the production and release of substances that act as intercellular messengers. The latter include interleukin-1 (Schmidt et al., 1984; Elias et al., 1988; Becker et al., 1989), tumor necrosis factor (Becker et al., 1989; Beutler et al., 1985; Kunkel et al., 1986), platelet-derived growth factor (Ross, 1987), and oxygenated metabolites of arachidonic acid (AA; see Chauncey et al., 1988. Ogle et al., 1988; Nichols et al., 1988; Garcia et al., 1989). These substances may simultaneously enhance the defensive reaction by activating and recruiting circulating immune cells (Samuelsson et al., 1987) and promote a pathophysiological series of events that ultimately results in a persistent inflammatory response and fibrogenesis (Morley et al., 1979). The mechanism by which the interaction of an inhaled foreign particle with the AM elicits these responses is unclear. However, it is apparent that, while the inhalation of some types of particles has little effect on lung function, the inhalation of other types may result in the initiation of a debilitating disease process. For example, examination of lung sections from coal miners suggests that fibrosis is directly related to the quartz content of the dust retained in the lung. Thus coal dust with a low quartz content produces focal lesions with minimal fibrosis, while coal dust with a high quartz content is associated with progressive massive fibrosis (Douglas et al., 1986). As a result, it has been suggested that certain physicochemical characteristics of inhaled particles are important determinants of their relative pathogenicity (Valiyathan et al., 1988). In particular, it has been reported that the concentration of silanol groups on the surface of silica particles is a factor in the relative biological toxicity of these particles as determined by hemolytic activity (Pandurangi et al., 1990). In addition, it has been suggested that oxygenderived radicals generated in aqueous suspensions of freshly crushed quartz particles may be important in membrane lipid peroxidation and the fibrogenicity of inhaled quartz dust (Shi et al., 1988 ). In order to further clarify the possible role of surface constituents of dust particles on pathophysiology in the lung, we studied the effect of various dusts and dust treatments on AA metabolism in the AM. We specifically evaluated the effect of various dusts on the production of prostaglandin E2 (PGE2), thromboxane A2 (TXA2), and leukotriene B4 (LTB4) for several reasons. First, these eicosanoids are major metabolites of the AM (Baiter et al., 1989). In addition, PGE2 and TXA2 appear to be major regulators of the production and action of the fibrogenic cytokines (Kunkel et al., 1986; Hocking et al., 1990). Finally, relatively little is known about the effect of mineral dust on the production of

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PGE2 and TXA2. The results of these studies suggest that experimental manipulation of surface constituents on both silica and coal dust particles may be related to the ability of the particle to stimulate the production of eicosanoids by AM. These findings support the concept that the chemical characteristics of the surface of inhaled dust particles may be involved in their relative ability to promote chronic lung disease. METHOD Downloaded by [University of Florida] at 10:46 06 November 2015

Preparation of Dust

Stock bituminous coal dust from the Pittsburgh seam was provided by the Department of Mineral Engineering, Pennsylvania State University. Freshly ground coal dust was prepared for in vitro exposure studies by grinding stock dust for 10 min in a zirconium ball mill (IEC, model P7). Freshly ground dust was then retested in the same experimental protocol (described below) after being shelved in closed containers for at least 30 d (hereafter referred to as "stale" coal dust). The chemical characteristics of these dusts have been described (Dalai et al., 1988). Respirable crystalline dust of alpha-quartz (Min-U-Sil, found in association with rock and coal mining operations) and amorphous, fumed silica dust (Cab-O-Sil, found in association with high-temperature processing of siliceous materials such as glass blowing) were provided by Dr. Pedro Bolsaitis. Each type of silica was provided in an untreated state and following calcination at 500 and 1100°C. This heating process combines free surface silanol groups to form stable siloxane bonds. These silica preparations were introduced into the in vitro exposure system 5 d ("fresh" calcined) and 8 wk ("stale" calcined) after calcination. Approximately 85% of the particles in both coal and silica dust preparations were between 2 and 7 fim in diameter. The chemical and cytotoxic characteristics of the silica dusts used in our study have been described previously (Pandurangi et al., 1990). AM Harvest Alveolar cells were collected by bronchoalveolar lavage as previously described (Kuhn et al., 1990). Briefly, female rats (Fischer F344 strain, 180-200 g, Charles River Laboratories, Kingston, N.Y.) were anesthetized with sodium pentobarbital (10 mg, ip) and then exsanguinated through the abdominal aorta. Phosphate-buffered saline containing 1 /¿g/ml EDTA was instilled into the lungs via a trachéal cannula and cells were collected in five 8-10 ml washes. Cells were centrifuged (250 x g, 10 min), washed twice with medium 199 (without phenol red, Sigma Chemical Company, St. Louis, Mo.), pooled, and finally resuspended in M199 containing 0.7% HEPES, 3 g/l bovine serum albumin,

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100 U/ml penicillin, and 10 /xg/ml streptomycin. Cells were enumerated in a hemacytometer and viability (always >95%) was determined by trypan blue exclusion. Cells were diluted in M199 to a final concentration of 5 x 105 cells/ml. One milliliter of cell suspension was then placed in each well of a 24-well culture plate. Nonadherent cells were removed after 1-h of preincubation (37°C in a humidified atmosphere of 5% CO2 in air) and fresh medium was added to each well.

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Experimental Protocol

Following the 1 h attachment period, cells were washed and AA (1.3 /ig/well) was added to each well. This incubation with AA was conducted in order replenish endogenous AA utilized during the exaggerated eicosanoid production that occurs during cell attachment (Kouzan et al., 1988). The incubation was continued for 24 h. Unincorporated AA was then removed and fresh medium was added to the wells. Various dust preparations were suspended in M199 (1 mg dust/ml) and sonicated to ensure uniform dispersion. One hundred microliters of each suspension was added to the appropriate wells. Previous dose-response studies (data not shown), in which trypan blue was added to cells following dust exposure, have indicated that this concentration is not cytotoxic. Control wells received 100 /¿I of M199. Following a final 24 h of incubation, culture medium was removed and acidified to pH 3.0 with 1 N HCI. Eicosanoids were extracted twice with 2 ml ethyl acetate/cyclohexane (1 : 1). Extracts were stored at - 2 0 c C until analysis of eicosanoid levels by specific radioimmunoassay (RIA). Eicosanoid RIA

Extracts of culture medium were subjected to RIA of specific eicosanoids as previously described (Demers, 1983). RIA reagents were purchased from Advanced Magnetics, Inc. (Boston, Mass.). The antibodies utilized in the assay of PGE2, thromboxane B2 (TXB2, the stable metabolite of TXA2), and LTB4 showed less than 1% cross-reactivity with other eicosanoids, with the exception of PGE2 antibody, which showed 52% cross-reactivity with PG Statistical Analysis

Mean values in four to five separate experiments were derived from measurements of at least three wells per treatment. Statistical differences in mean eicosanoid levels between control and treatment groups was determined by the paired Student's í test. Nominal p values less than .05 were considered to represent significant differences between groups.

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RESULTS

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In Vitro Exposure to Coal Dust

As seen in Figure 1, in vitro exposure of normal rat AM to "fresh" coal dust resulted in increased production of PGE2. However, exposure of AM to "stale" dust resulted in a significant decrease in PGE2 production compared with control AM. Mean (±SEM) values for PGE2 levels in control, "fresh," and "stale" groups were 273 (±66), 547 (±194), and 202 (±45) pg/ml, respectively. Exposure of AM to "fresh" coal dust resulted in a significant increase in TXA2 production compared with control, while exposure to "stale" dust produced TXA2 levels that were not different from control. Mean (±SEM) values for TXB2 levels in control, "fresh," and "stale" groups were 146 (±36), 190 (±64), and 131 (±26) pg/ml, respectively. Exposure of AM to either "fresh" or "stale" coal dust had no effect on LTB4 production [633 (±189) pg/ml in the control group]. In Vitro Exposure to Silica Dust

Amorphous fumed silica (Cab-O-Sil) was a more potent stimulator of AM eicosanoid production than was coal dust (Fig. 2). Exposure of AM to Cab-O-Sil significantly increased AM PGE2 production from 572 (±72) to 1830 (±520) pg/ml. Likewise, exposure of AM to Cab-O-Sil significantly increased TXA2 production from 112 (±17) to 553 (±120) pg/ml. LTB2 production was also increased from 260 (±30) to 333 (±14) pg/ml by exposure of AM to Cab-O-Sil. However, exposure of AM to Cab-O-Sil that had been calcined to 1100°C resulted in eicosanoid levels in culture medium that were not significantly different from control. 300-1

200-

c o

Ü

100-

PGE2

TXB2

LTB4

FIGURE 1. Effect of in vitro exposure to freshly ground or "stale" coal dust on eicosanoid production in rat AM. Mean eicosanoid levels in each group are expressed as percent of control values for each eicosanoid. Statistical differences in mean values were determined by the paired Student's í test (*p < .05 vs. control).

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D. C. KUHN AND L. M. DEMERS

I

500-

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O Ü

E3 Untreated silica 0

Calcined silica

250-

PGE2

TXB2

LTB4

FIGURE 2. Effect of in vitro exposure to silica (Cab-O-Sil) dust on eicosanoid production in rat AM. Untreated silica and silica calcined to 1100°C were tested. Mean eicosanoid levels in each group are expressed as percent of control values for each eicosanoid. Statistical differences in mean values were determined by the paired Student's f test (*p < .05 vs. control).

Comparison of Amorphous and Crystalline Silica

As in the series of studies described above, PGE2 and TXB2 production were significantly increased when normal rat AM were exposed to untreated silica particles in vitro (Table 1). Untreated Cab-O-Sil was a significantly more potent stimulator of eicosanoid production than was untreated Min-U-Sil. AM exposed to Min-U-Sil particles that had been recently calcined at 500 or 1100°C for 6 h produced PGE2 and TXB2 at TABLE 1. Comparison of the Effect of In Vitro Exposure to Uncalcined or Calcined Silica Dusts (Min-U-Sil or Cab-O-Sil) on Eicosanoid Production in Rat AM

Dust type "Fresh" silica Cab-O-Sil Cab-O-Sil 500 Cab-O-Sil 1100 Min-U-Sil Min-U-Sil 500 Min-U-Sil 1100 "Stale" silica Cab-O-Sil Cab-O-Sil 500 Cab-O-Sil 1100 Min-U-Sil Min-U-Sil 500 Min-U-Sil 1100

PGE2 (% of control)

TXB2 (% of control)

249 (26)a 226 (24)a 122 (10) 181 (19)a 124 (15)a 106 (9)

294 (28)a 261 (21)a 79(9) 202 (25)a 108 (11)a 98(7)

398 (23)a 399 (31)a 102 (15) 229 (9)a 105 (10)a 97(8)

701 (38)a 704 (36)a 103 (10) 375 (21)a 216 (14)a 101 (6)

Nofe. Mean eicosanoid levels are expressed as percent (±SEM) of control values. Significant at p < .05 versus control.

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levels that were not significantly different from control. Exposure of AM to Cab-O-Sil calcined at 500°C resulted in a slight reduction in eicosanoid production compared to untreated Cab-O-Sil; however, eicosanoid production was still significantly increased compared with control AM. Calcination of Cab-O-Sil to 1100°C resulted in the elimination of its ability to stimulate PGE2 and TXB2 production by AM. Studies conducted 8 wk following calcination of quartz particles ("stale" quartz) produced qualitative results similar to those studies conducted shortly after calcination of quartz particles. Untreated CabO-Sil increased PGE2 and TXB2 production to a greater extent than untreated Min-U-Sil. Calcination of Min-U-Sil, but not Cab-O-Sil, at 500°C reduced its ability to stimulate PGE2 and TXB2 production. Calcination of Cab-O-Sil and Min-U-Sil at 1100°C resulted in PGE2 and TXB2 production that was not significantly different from control. LTB4 levels were not determined in this series of experiments. DISCUSSION AND CONCLUSIONS In our previous studies (Kuhn et al., 1990), we characterized changes in AM eicosanoid production as a result of in vivo exposure to "stale" coal dust. We speculated that the observed alterations in eicosanoid production could be expected to contribute to inflammatory processes in the lung and perhaps the pathophysiological sequelae of coal workers' pneumoconiosis (CWP). However, the results of several recent studies lead us to reexamine the effects of mineral dust on AM eicosanoid production with the focus on dust surface chemical characteristics. Based on the work of Retkofsky (1982), which demonstrated that coal contains carbon-centered organic free radicals, Jafari et al. (1988) examined preserved lung tissue from coal miners by electron spin resonance (ESR) spectroscopy and found a positive correlation between free radicals in the lung tissues and the severity of CWP. Subsequently, this group (Dalai et al., 1988; Vallyathan et al., 1988) demonstrated that free radicals are released when coal or silica dust are freshly fractured and that these radicals decay as the dust "ages." The biological activity of these radicals was found to decay in parallel with their ESR signal. At least one component of the free radical activity has been identified as the OH radical (Shi et al., 1988). Additional studies by Pandurangi et al. (1990) using infrared spectroscopy showed that silanol groups on the surface of silica particles were involved in the cytotoxicity of silica as measured by a hemolysis assay. Together with the studies of other investigators showing that chemical modification of dust surfaces alters their ability to activate AM phagocytosis (Jakab et al., 1990), inflammation, and fibrosis (Weissner et al., 1990), these findings strongly suggest that the chemical characteristics of mineral dust are a crucial determinant of their biological activity. However, the possible relationship be-

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tween mineral dust-associated radicals and the production of eicosanoids by the AM has not been explored. Additional studies by Pandurangi et al. (1990) assessed differences in the cytotoxicity of silica as a result of treatment designed to neutralize radicals on the surface of the particle. In these studies, the concept that free silanol groups are directly involved in red blood cell (RBC) lysis was tested by assessing the hemolytic activity of untreated silica and silica calcined to 500 or 1100°C. The results of these studies suggest that the hemolytic activity of silica is directly related to free OH group concentration and that calcination to 1100CC eliminates hemolytic activity. In addition, these investigators showed that the hemolytic activity of silica calcined at 500°C returns to baseline following 10-20 d of rehydroxylation, while that of silica calcined at 1100°C remains reduced for several months after calcination. Activation of phagocytic receptors on AM has been shown to increase TXA2 production in rat AM (Kouzan et al., 1985), while activation of human AM by calcium ionophore has been shown to increase PGE2 production (Baiter et al., 1988). However, Brown et al. (1988) found that silica (1 mg/ml) had no effect on PGE2 production by human AM. These apparently contradictory results may be the result of a difference in the dose of silica used in various studies. For example, in dose-response studies (data not shown), we have found that this concentration of silica (1 mg/ml) actually inhibits PGE2 production in rat AM, possibly as a result of cytotoxicity. Likewise, Englen et al. (1989) have shown that the release of cyclooxygenase products declines with increasing silica concentrations above 500 (iglvn\. Furthermore, the studies of Marks and Nagelschmidt (1959) established in vitro toxic doses of several types of silica dust, based on the dehydrogenase method, at less than 100 /¿g/3 x 106 macrophages. Nonetheless, it is apparent from the results of each of these studies that silica dust is a potent, biologically active respirable dust and that its biological activity may be associated with alterations in AM eicosanoid production. The purpose of the present study was to determine if differences in respirable dust surface chemistry can influence the ability of dust to alter AM eicosanoid production. Alterations in lung eicosanoid production have been implicated in the pathophysiology of several inflammatory and neoplastic lung diseases including asbestosis (Garcia et al., 1989), asthma (Godard et al., 1982), experimental acute lung injury and microvascular damage (Deffenbach et al., 1987), and adult respiratory distress syndrome (Stephenson et al., 1988). The possible mechanisms for a generalized increase in AA metabolism in inflammatory lung disease may include the activation of AM phospholipase through the stimulation of phagocytic receptors (Williams et al., 1984), the cooxidation of AA as a result of the generation of reactive oxygen radicals during the respiratory burst (Sporn et al., 1988; Fridovich and

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Porter, 1981), and/or the release of lysosomal phospholipase, resulting in increased unesterified AA for conversion to eicosanoids. As a result of increased AA metabolism, several proinflammatory events are likely to occur. These include increased vascular and bronchial smooth muscle contractility, increased extravasation and recruitment of additional circulating immune cells to the site of invasion, alterations in AM cytokine production, and increased lipid peroxidation. The continual stimulation of AA metabolism, as well as the activation of the production of other mediators of the inflammatory process (e.g., platelet activating factor, components of complement), may then contribute to chronic inflammation and pathological consequences including fibrosis. The results of the present study suggest that the chemical characteristics of the surface of dust particles may indeed influence their biological effects. We have observed striking differences in in vitro exposure studies in the ability of "fresh" coal dust to alter AM eicosanoid production compared to "stale" dust. Thus while exposure to "fresh" dust significantly increases PGE2 and TXB2 production in rat AM, exposure to "stale" dust results in a decrease in the production of these metabolites. Likewise, when normal AM were exposed to untreated silica in vitro, PGE2 and TXB2 were significantly increased: Exposure to Cab-O-Sil resulted in a somewhat greater increase in PGE2 and TXB2 production than did exposure to Min-U-Sil. Calcination of Min-U-Sil to 500°C resulted in a significant reduction in its ability to increase eicosanoid production; however, no such reduction was apparent with calcination of Cab-O-Sil to 500°C. Calcination of both silicas to 1100°C resulted in the elimination of their ability to alter AM eicosanoid production. It is important to note that Pandurangi et al. (1990) also found differences in both the chemical and hemolytic properties of Cab-O-Sil and Min-U-Sil. These investigators reported that the intensity of an ESR broad band (3000-3700 cm' 1 ) identified with hydrogen-bonded OH surface groups was considerably more intense with samples of Cab-O-Sil as compared to Min-U-Sil. In addition, the hemolytic activity of Cab-O-Sil was an order of magnitude greater than that of Min-U-Sil. These differences may be related to the physical characteristics of the two types of silica, as Cab-O-Sil has a specific surface area that is about 40 times greater than that of Min-USil. Furthermore, these investigators demonstrated a reduction in both the broad-band ESR signal of the silica preparations and the hemolytic activity with calcination to 1100°C. The results of our studies, in which calcined silica was allowed to rehydroxylate in room air for 8 wk, also find some parallels in the studies of Pandurangi et al. (1990). These investigators found that the hemolytic activity of both Cab-O-Sil and Min-U-Sil calcined to 1100°C remained reduced compared to untreated dust for at least 190 d after

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D. C. KUHN AND L. M. DEMERS

heating. However, when Cab-O-Sil was calcined to less than 1100°C (950 and 800°C), hemolytic activity recovered to that of untreated silica within 18 d of treatment. In our studies neither Min-U-Sil or Cab-O-Sil that had been calcined to 1100°C was able to stimulate eicosanoid production 8 wk after calcination. However, Cab-O-Sil that had been calcined to only 500°C augmented eicosanoid production to a degree similar to untreated Cab-O-Sil 8 wk after calcination. On the contrary, while these investigators found a reduction in cytotoxicity when "stale" silica was compared to freshly calcined silica, our data showed increased eicosanoid production with "stale" silica. A possible explanation for this contradiction is that cytotoxicity and bioactivity (as measured by eicosanoid production) each have a discrete relationship to silica surface chemistry, rather than being directly related phenomena. The practical implications of our findings are difficult to assess at present. In particular, it is likely that individuals in the mine environment are exposed to both "fresh" and "stale" dust as a result of the mining process and dust reentrainment, respectively. In addition, different job sites within the mine are likely to involve different levels of relative, as well as absolute, dust exposure. For example, the roof bolter, who works in an area where rock dust is at a relatively high concentration, is more likely to be exposed to predominantly silica dust. Likewise, the continuous miner operator is likely to be exposed to predominantly "fresh" dust while an individual who works ¡n an area distant from the mining operation is likely to inhale relatively less freshly fractured dust. Nonetheless, our findings support the concept that the chemical characteristics of mineral dust are important in the relative production of inflammatory and fibrotic compounds by the alveolar macrophage. The further clarification of the role of dustassociated radicals could both increase our understanding of the etiology of mineral dust-induced lung disease and suggest further strategies for intervention (e.g., antioxidants, radical scavengers, eicosanoid antagonists) in the pathophysiological consequences of occupational dust inhalation. REFERENCES Balter, M. S., Eschenbacher, W.L., and Peters-Golden, M. 1988. Arachidonic acid metabolism in cultured alveolar macrophages from normal, atopic and asthmatic subjects. Am. Rev. Respir. Dis. 138:1134-1138. Balter, M. S., Toews, G. B., and Peters-Golden, M. 1989. Different patterns of arachidonate metabolism in autologous human blood monocytes and alveolar macrophages. J. Immunol. 142:602608. Becker, S., Devlin, R. B., and Haskill, J. S. 1989. Differential production of tumor necrosis factor, macrophage colony stimulating factor and interleukin-1 by human alveolar macrophages. J. Leuk. Biol. 45:353-361.

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Beutler, B., Greenwald, D., Hulmes, J. D., Chang, M., Pan, Y.-C. E., Mathison, J., Ulevitch, R., and Cerami, A. 1985. Identity of tumor necrosis factor and the macrophage-secreted factor cachectin. Nature 316:552-554. Brown, C. P., Monick, M., and Hunninghake, G. W. 1988. Fibroblast proliferation induced by silicaexposed human alveolar macrophages. Am. Rev. Respir. Dis. 138:85-89. Chauncey, J. B., Simon, R. H., and Peters-Golden, M. 1988. Rat alveolar macrophages synthesize leukotriene B4 and 12-hydroxyeicosatetraenoic acid from alveolar epithelial cell-derived arachidonic acid. Am. Rev. Respir. Dis. 138:928-935. Dalai, N. S., Suryan, M. M., Jafari, B., Shi, X., Vallythan, V., and Green, F. H. Y. 1988. Electron spin resonance detection of reactive free radicals in fresh coal dust and quartz and its implications to pneumoconiosis and silicosis. In Respirable Dust in the Mineral Industries, eds. R. L. Frantz and R. V. Ramani, pp. 24-29. University Park, Pa.: Pennsylvania State University Press. Deffenbach, M. E., Lakshminarayan, S., Kirk, W., and Butler, J. 1987. Bronchial circulation and cyclooxygenase products in acute lung injury. J. Appl. Physiol. 63:1083-1088. Demers, L. M. 1983. Prostaglandins, thromboxane and leukotrienes. In Laboratory Medicine, G. J. Race, pp. 1-21. Philadelphia: Harper and Row. Douglas, A. N., Robertson, A., Chapman, J. S., and Ruckley, V. A. 1986. Dust exposure, dust recovered from the lung, and associated pathology in a group of British coalminers. Br. J. Ind. Med. 43:795-801. Elias, J. A., Gustilo, K., and Freundlich, B. 1988. Human alveolar macrophage and blood monocyte inhibition of fibroblast proliferation. Am. Rev. Respir. Dis. 138:1595-1603. Englen, M. D., Taylor, S. M., Laegreid, W. W., Liggitt, H. D., Silflow, R. M., Breeze, R. G., and Leid, R. W. 1989. Stimulation of arachidonic acid metabolism in silica-exposed alveolar macrophages. Exp. Lung Res. 15:511-526. Fridovich, S. E., and Porter, N. A. 1981. Oxidation of arachidonic acid in micelles by Superoxide and hydrogen peroxide. J. Biol. Chem. 256:260-265. Garcia, J. G. N., Griffith, D. E., Cohen, A. B., and Callahan, K. S. 1989. Alveolar macrophages from patients with asbestos exposure release increased levels of leukotriene B4. Am. Rev. Respir. Dis. 139:1494-1501. Godard, P., Chaentreuil, J., Damon, M., Coupe, M., Flandre, O., Crastes de Paulet, D., and Miche, F. 1982. Functional assessment of alveolar macrophages: Comparison of cells from asthmatics and normal subjects. J. Allergy Clin. Immunol. 70:88-93. Hocking, D. C., Phillips, P. G., Ferro, T. J., and Johnson, A. 1990. Mechanisms of pulmonary edema induced by tumor necrosis factor-α. Circ. Res. 67:68-77. Jafari, B., Dalai, N. S., Vallyathan, V., and Green, F. H. Y. 1988. Detection of organic radicals in coaldust exposed lung tissue and correlations with their histological parameters. In Respirable Dust in the Mineral Industries, eds. R. L. Frantz and R. V. Ramani, pp. 223-225. University Park, Pa.: Pennsylvania State University Press. Jakab, G. J., Risby, T. H., Sehnert, S. S., Hmieleski, R. R., Farrington, J. E. 1990. Suppression of alveolar macrophage membrane receptor-mediated phagocytosis by model and actual particle-adsorbate complexes. Initial contact with the alveolar macrophage membrane. Environ. Health Perspect. 86:337-344. Kouzan, S., Gallagher, J. E., Eling, T., and Brody, A. R. 1985. Binding of iron beads or sialic acid residues on macrophage membranes stimulates arachidonic acid metabolism. Lab. Invest. 53:320-327. Kouzan, S., Nolan, R. D., Fournier, T., Bignon, J., Eling, T. E., and Brody A. R., 1988. Stimulation of arachidonic acid metabolism by adherence of alveolar macrophage to a plastic substrate. Am. Rev. Respir. Dis. 137:38-43. Kuhn, D. C., Stanley C. F., El-Ayouby, N., and Demers, L. M. 1990. The effect of in vivo coal dust exposure on arachidonic acid metabolism in the rat alveolar macrophage. J. Toxicol. Environ. Health 29:157-168. Kunkel, S. L., Wiggins, R. C., Chensue, S. W., and Larrick, J. 1986. Regulation of macrophage tumor necrosis factor by prostaglandin E2. Biochem. Biophys. Res. Commun. 137:404-410.

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Influence of mineral dust surface chemistry on eicosanoid production by the alveolar macrophage.

It has been suggested that radicals on the surface of dust particles are key chemical factors in the pathophysiology that results from the occupationa...
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